CN113149929B - Pleuromutilin derivative with 1,3, 4-oxadiazole side chain and preparation and application thereof - Google Patents
Pleuromutilin derivative with 1,3, 4-oxadiazole side chain and preparation and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pleuromutilin derivative with a 1,3, 4-oxadiazole side chain, and preparation and application thereof. The pleuromutilin derivative with the 1,3, 4-oxadiazole side chain is a compound of the formula 2 or pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer, tautomer or mixture of any proportion of the compound of the formula 2 or pharmaceutically acceptable salt thereof, including racemic mixtures. The pleuromutilin derivative has good antibacterial activity, is particularly suitable for being used as a novel antibacterial drug for systemic infection of animals or humans, and has good water solubility.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pleuromutilin derivative with a 1,3, 4-oxadiazole side chain, and preparation and application thereof.
Background
As one of the major pathogens of high morbidity and mortality, multi-drug resistant staphylococcus aureus (MRSA) often causes healthcare-related infections, posing a serious threat to human health worldwide. Thus, there is an urgent need to develop new antibiotics with new modes of action for the treatment of infections caused by multi-drug resistant staphylococcus aureus (MRSA).
Natural products have been playing an important role in dealing with human diseases, especially in the field of infectious diseases. Despite some drawbacks, various natural products or derivatives thereof have been developed and approved for use as antibacterial agents, such as aztreonam, vancomycin, tigecycline, and penicillin G. The development of new antimicrobial agents from natural products or semisynthetic derivatives thereof remains the most effective method to combat MRSA infections.
Pleuromutilin (formula 1) is a natural tricyclic diterpenoid compound and is produced by culturing Pleurotus ostreatus Pleurotus mutilus and Pleurotus Passeckerianus, and has eight three-dimensional center extremely rigid structures such as 5-6-8 tricyclic carbon skeletons and a glycolic acid chain of C (14).
Studies have shown that pleuromutilins and derivatives thereof exhibit potent antibacterial activity against gram-positive bacteria and are distinguished from other antibacterial agents that are widely used in clinical settings in that pleuromutilins and derivatives thereof inhibit bacterial protein synthesis by binding to the V region of the Peptide Transferase Center (PTC) of the bacterial 50s ribosomal subunit 23s RNA. Due to the unique mechanism of action, pleuromutilins and derivatives thereof have a low incidence of cross-resistance with other antibacterial agents and a low propensity of bacteria to develop bacterial resistance, while not substantially interacting with mammalian cell ribosomes nor interfering with protein synthesis in eukaryotic cells. The researches pay attention to that the side chain on C14 in the pleuromutilin structural molecule can penetrate into the hydrophobic group of the ribosomal subunit to improve the antibacterial activity of the pleuromutilin structural molecule. Thus, modification of the C14 side chain by chemical means has been an important means of increasing the drug-forming properties of pleuromutilin derivatives.
To date, by modifying its C14 side chain, the antibacterial drugs successfully marketed have been the veterinary antibacterial drugs Tiamulin (Tiamulin), valnemulin (Valnemulin), human topical Retapamulin (Retapamulin) and human pharmaceutical lefmulin (Lefamulin) for the treatment of community-acquired bacterial pneumonia (CABP) on the market by FDA approval in 2019.
Compared with tens of medicines which are successfully developed based on the same parent nucleus, such as penicillin, cephalosporin and sarcin, the pleuromutilin only successfully develops four antibacterial medicines, and the drug-resistant bacteria aiming at the pleuromutilin antibacterial medicines are not seen. Therefore, the development of more pleuromutilin antibacterial agents is necessary.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the primary aim of the invention is to provide a pleuromutilin derivative with a 1,3, 4-oxadiazole side chain, which has good antibacterial activity and is particularly suitable for being used as a novel antibacterial drug for systemic infection of animals or humans.
It is another object of the present invention to provide a process for the preparation of the above-mentioned pleuromutilin derivatives having a 1,3, 4-oxadiazole side chain.
It is a further object of the present invention to provide the use of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain as described above.
The invention aims at realizing the following technical scheme:
a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain, being a compound of formula 2 or a pharmaceutically acceptable salt thereof, and a solvate, enantiomer, diastereomer, tautomer of said compound of formula 2 or a pharmaceutically acceptable salt thereof, or mixtures thereof in any ratio, including racemic mixtures:
wherein R is R 1 Or (b)
R 1 Is one of a hydrogen atom, a furyl group, a thienyl group, a phenyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group and a pyrazinyl group;
R 2 is one of methyl, trifluoromethyl, amino, hydroxyl, hydrogen, fluorine, chlorine and bromine;
R 3 is one of methyl, nitro, amino, hydrogen atom, fluorine atom, chlorine atom and bromine atom;
R 4 is methyl groupOne of trifluoromethyl, amino, dimethylamino, hydroxyl, methoxy, hydrogen, fluorine, chlorine and bromine;
and R is 2 、R 3 、R 4 Cannot be hydrogen atoms at the same time;
preferably, said R 2 Is methyl, R 3 Is a hydrogen atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is methyl, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is methyl;
or R is 2 Is trifluoromethyl, R 3 Is a hydrogen atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is trifluoromethyl;
or R is 2 Is a hydrogen atom, R 3 Is amino, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is amino;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is dimethylamino;
or R is 2 Is a hydrogen atom, R 3 Is nitro, R 4 Is a hydrogen atom;
or R is 2 Is hydroxy, R 3 Is a hydrogen atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is hydroxyl;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is methoxy;
or R is 2 Is a fluorine atom, R 3 Is a hydrogen atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a fluorine atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is a fluorine atom;
or R is 2 Is a chlorine atom, R 3 Is a hydrogen atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a chlorine atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is a chlorine atom;
or R is 2 Is a hydrogen atom, R 3 Is a bromine atom, R 4 Is a hydrogen atom;
or R is 2 Is a hydrogen atom, R 3 Is a hydrogen atom, R 4 Is a bromine atom;
specific groups of the above preferred structural compounds are summarized in table 1:
table 1 Compound numbering and specific groups
The pharmaceutically acceptable salt is a salt formed by a compound of formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid;
the pharmaceutically acceptable salt preferably has the following structural formula:
the preparation method of the pleuromutilin derivative with the 1,3, 4-oxadiazole side chain comprises the following steps:
(1) Reacting pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate I with a structure shown in a formula 3;
(2) Reacting carboxylic acid serving as a raw material with absolute ethyl alcohol to obtain an intermediate II with a structure shown in a formula 4;
(3) Reacting the intermediate II prepared in the step (2) with hydrazine hydrate to obtain an intermediate III with a structure shown in a formula 5;
(4) Reacting the intermediate III prepared in the step (3) with carbon disulfide to obtain an intermediate IV (corresponding compounds 1 c-28 c in the embodiment of the invention) shown in a formula 6;
(5) Further activating the intermediate I prepared in the step (1) by sodium iodide, and then reacting with the intermediate IV prepared in the step (4) to obtain the pleuromutilin derivative with the 1,3, 4-oxadiazole side chain shown in the formula 2;
the intermediates I, II, III and IV respectively have structural formulas 3-6:
the molar ratio of the tosyl chloride to the pleuromutilin in the step (1) is preferably 1.1:1;
the molar ratio of the carboxylic acid to the absolute ethanol in the step (2) is preferably 1:1.1;
the reaction in the step (3) adopts absolute ethyl alcohol as a solvent, the mol ratio of the intermediate II to hydrazine hydrate is preferably 1:1, and the reaction condition is preferably 25-40 ℃ for 2-3 h;
the specific operation of the reaction described in step (4) is preferably:
dissolving potassium hydroxide by using 95% (v/v) ethanol as a solvent, adding an intermediate III under ice bath, then dropwise adding carbon disulfide, and heating and refluxing for 3-4 hours at 78-80 ℃;
the consumption of 95% (v/v) ethanol is preferably 5-20 times of the mass of the intermediate III, the molar ratio of potassium hydroxide to the intermediate III is preferably 1.2:1, and the molar ratio of carbon disulfide to the intermediate III is preferably 1.1:1;
the specific operation of activation described in step (5) is preferably:
acetonitrile is used as a solvent to firstly dissolve the intermediate I, then sodium iodide and alkali are added, and heating reflux is carried out for 1-3 h at 78 ℃;
the dosage of acetonitrile is preferably 30-40 times of the mass of the intermediate I, the molar ratio of the alkali to the intermediate I is preferably 2:1, and the molar number of sodium iodide is preferably 10% of the molar number of the alkali;
the alkali is preferably sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;
the reaction condition in the step (5) is preferably 78-80 ℃ heating reflux for 1-3 h;
the synthetic route is shown in the following formula:
the application of the pleuromutilin derivative with the 1,3, 4-oxadiazole side chain in the preparation of antibacterial products;
the antibacterial product is preferably a medicament for treating infectious diseases;
the antibacterial product is further preferably an antibacterial agent for treating infectious diseases caused by gram-positive bacteria;
the infectious diseases are infectious diseases caused by infection of human or animals by drug-resistant staphylococcus aureus or multi-drug resistant bacteria;
the medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents;
the preparation of the medicine comprises a plurality of clinical medicine dosage forms, such as tablets, injection, liposome nano-particles, controlled release agents and the like;
an antibiotic drug comprising an effective amount of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain, the balance being a pharmaceutical adjuvant or other compatible drug;
the pharmaceutical excipients are conventional pharmaceutical excipients such as solvents, disintegrants, flavoring agents, preservatives, colorants, binders and the like;
the other compatible medicines are prepared by taking an effective dose of pleuromutilin derivative with a 1,3, 4-oxadiazole side chain as a medicine raw material and then matching with other natural medicines or chemicals;
compared with the prior art, the invention has the following advantages:
(1) The pleuromutilin derivatives provided by the invention are novel compounds which are not reported.
(2) According to the invention, through extensive and intensive research, a large number of pleuromutilin derivatives with 1,3, 4-oxadiazole side chains with brand new structures are synthesized, and wide antibacterial activity screening is carried out, so that the compounds have good in-vitro antibacterial activity, and have the advantage of low preparation cost of Valnemulin and Retapamulin, thus being particularly suitable for being used as novel antibacterial drugs for preventing and treating bacterial infectious diseases of human or animals, especially infectious diseases caused by drug-resistant staphylococcus aureus.
(3) The pleuromutilin derivative with the 1,3, 4-oxadiazole side chain prepared by the invention has good water solubility.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of Compound 2.
FIG. 2 is a nuclear magnetic resonance spectrum of Compound 3.
FIG. 3 is a nuclear magnetic resonance image of compound 15.
FIG. 4 is a nuclear magnetic resonance image of compound 19.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
In embodiments, R-COOCH 2 CH 3 Wherein R is R 1 Or (b)
Wherein the specific radicals R 1 、R 2 、R 3 、R 4 See Table 1, all commercially available, as well as other reagents.
Example 1
(1) Intermediate I preparation: 10.0g (26.5 mmol) of pleuromutilin was dissolved in 20ml of pyridine and placed in an ice bath; dissolving 5.6g (29.2 mmol) of p-toluenesulfonyl chloride in 10ml of pyridine, slowly adding the pleuromutilin pyridine solution, stirring the mixed solution for 3h in an ice bath, sequentially adding 50ml of ice water and 50ml of chloroform, transferring to a separating funnel, shaking, standing and layering; the organic phase is taken and washed by 100ml of sulfuric acid with the concentration of 4mol/L, 100ml of saturated sodium bicarbonate solution and 100ml of deionized water in sequence; evaporating the organic solution from the washed organic phase under reduced pressure, adding 20ml of isopropanol into the residual solid, heating for dissolution, cooling again, precipitating a large amount of white powder, carrying out suction filtration, washing filter residues with isopropanol, and drying to obtain an intermediate I with a structure shown in a formula 3, wherein the yield is 81%;
(2) Intermediate II1a preparation: 155.5mmol of carboxylic acid (R-COOCH) 2 CH 3 Wherein R is H) is dissolved in 10ml of absolute ethyl alcohol, after the mixed solution is stirred for 3min in an ice bath, 0.15ml of concentrated sulfuric acid is slowly added, and the mixture is heated and refluxed for 4H at 115 ℃; pouring the reaction solution into a separating funnel, adding 30ml of dichloromethane for extraction, washing twice with deionized water, drying with anhydrous sodium sulfate after washing, and taking an organic phase; the obtained organic phase is evaporated to dryness in a rotating way to obtain an intermediate II1a with a structure shown in a formula 4, and the yield is 76.72%;
(3) Intermediate III1b preparation: slowly adding 2.0g (40 mmol) of hydrazine hydrate into 10ml of absolute ethyl alcohol under mechanical stirring, slowly adding 40mmol of intermediate II, reacting at room temperature of 25 ℃ for 2 hours, then carrying out ice bath, precipitating a large amount of solids, and carrying out suction filtration; the product was dried in a vacuum desiccator with CaCl 2 Drying, and finally using P 2 O 5 Drying to obtain intermediate III1b with a structure shown in formula 5, wherein the yield is 70.88%;
(4) Compound 1c (intermediate IV-1) preparation: 0.67g (12 mmol) of potassium hydroxide was dissolved in 15ml of 95% (v/v) ethanol and 60.06mg (10 mmol) of intermediate III was added under ice-bath conditions; slowly dripping 0.84g (11 mmol) of carbon disulfide into the reaction system, and heating and refluxing at 80 ℃ after the dripping is finished; heating and refluxing for 3 hours, dropwise adding concentrated hydrochloric acid into a reaction system under ice bath condition, adjusting the pH value of the reaction system to 1, precipitating a large number of crystals, and carrying out suction filtration; the crystals were dried in a vacuum desiccator with CaCl 2 Drying, and finally using P 2 O 5 Drying gives compound 1c (intermediate IV-1) of the structure shown in formula 6 in 81.17% yield.
According to the methods of steps (1) to (4) (the molar amounts of the reactants, the reaction conditions, the purification and the like are the same), intermediate II2a to intermediate II28a (yield 75.55 to 88.64%), intermediate III2b to intermediate III28b (yield 62.84 to 74.25%), compound 2c to compound 28c (yield 75.35 to 86.54%) are obtained, respectively, and the yields of the intermediates are shown in Table 2.
EXAMPLE 2 preparation of 22-O- (1, 3, 4-oxadiazolyl) thioacetyl Miaolin (Compound 1)
2.13g (4 mmol) of intermediate I prepared in example 1 was dissolved in 81ml of acetonitrile, 0.12g (0.8 mmol) of anhydrous sodium iodide and 1.11g (8 mmol) of anhydrous potassium carbonate were added, the mixture was heated under reflux at 78℃for 2 hours, then 0.45g (4.4 mmol) of 1,3, 4-oxadiazole-2-thiol prepared in example 1 (intermediate IV-1) was added to the above system, the reaction was continued at 78℃for 3 hours, the reaction mixture was poured into a separating funnel, distilled water and 50ml of chloroform were added in sequence, and after shaking, the mixture was allowed to stand until it was separated, the organic phase was washed twice with aqueous sodium chloride (15% w/v) and dried with anhydrous sodium sulfate, and the organic phase was taken; the obtained organic phase is rotated and evaporated to dryness to obtain a mixture, the mixture is redissolved by methylene dichloride, 2g of 100-200 meshes of silica gel is added and fully mixed, after the solvent is volatilized, the crude product-silica gel powder mixture is purified by column chromatography (100-200 meshes of silica gel powder is used as a stationary phase, methylene dichloride: methanol=200:1 (V: V) is used as a mobile phase), and the pure product of 22-O- (1, 3, 4-oxadiazolyl) thioacetyl miaing forest is obtained, wherein the yield is 73.74%.
EXAMPLE 3 preparation of Compounds 2 to 28
According to the same manner as in example 2 (molar amount of each reactant, reaction condition, purification, etc. are the same as in example 2), only compound 1c (intermediate IV-1) was replaced with compounds 2c to 28c (intermediate IV-2 to intermediate IV-28), to obtain the corresponding products represented by formula 2, numbered 2 to 28 in this order. Wherein FIGS. 1-4 are nuclear magnetic resonance image spectra of compounds 2, 3, 15 and 19.
The preparation yields of the above compounds are summarized in Table 2.
Table 2 compound number and yield
Effect examples
(1) In vitro bacteriostasis experiment
The experiment used was broth dilution. Tiamulin is selected as the experimental control medicine. Tiamulin is a pleuromutilin antibiotic, and is one of ten world antibiotics for animals.
The strains used in the experiments were methicillin-resistant staphylococcus aureus ATCC43300 and staphylococcus aureus ATCC29213, clinical staphylococcus aureus (Staphylococcus aureus) AD3 and clinical staphylococcus aureus (s.aureus) 144 (clinical bacteria AD3 and 144 were isolated and identified in the pharmacological laboratory of the veterinary drug laboratory of the university of south china, as disclosed in the documents Zhe Z a, kang L a, gyz a, et al design, synthesis and biological activities of novel pleuromutilin derivatives with a substituted triazole moiety as potent antibacterial agents-science direct [ J ]. European Journal of Medicinal Chemistry, 2020).
Preparing a target compound stock solution: respectively precisely weighing 6.4mg of target compound, placing in a 10mL volumetric flask, dissolving with 0.25mL of LDMSO, adding 9.5mL of distilled water, fixing volume with 0.25mL of Tween 80, shaking thoroughly to obtain stock solution (6.4 mg/mL), sterilizing with 0.22 μm filter membrane, subpackaging with small tubes, and preserving at-20deg.C. The control drug tiamulin was also formulated as described above.
Preparing bacterial liquid: taking out the strain which is preserved at the temperature of minus 20 ℃ and inoculating the strain on a new MH flat plate, culturing for 24 hours at the temperature of 37 ℃, picking single colony, inoculating the single colony in MH culture medium, and culturing for 24 hours again; the single colony was transferred to sterile physiological saline and its turbidity was adjusted to 0.6McF, at which time the bacterial concentration was 10 6 CFU/mL。
MIC plate preparation: diluting the stock solutions of the target compounds (6.4 mg/mL) 10 times to obtain target compound solutions with a concentration of 640. Mu.g/mL; taking a sterile 96-well plate, adding 180 mu L of MH broth culture medium into a 1 st well, respectively adding 100 mu L of MH broth culture medium into a 2 nd to 10 th well, adding 20 mu L of antibacterial drug with the concentration of 640 mu g/mL into the 1 st well, uniformly mixing, taking 100 mu L of antibacterial drug into a 2 nd well, uniformly mixing, sucking 100 mu L of antibacterial drug into a 3 rd well, and then, analizing, sucking 100 mu L of antibacterial drug into a 12 th well for discarding. At this time, the drug concentration of each hole is as follows: 64. 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 μg/mL, three groups of drugs in parallel for each concentration.
Inoculating bacterial liquid: adding 100 μl of bacterial liquid into 1-12 wells to obtain final bacterial liquid concentration of about 5×10 5 CFU/mL, 1 st well to 12 th well drug concentrations were 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015 μg/mL, respectively. The inoculated 96-well plate is placed in a 37 ℃ incubator for culturing, and the growth condition of bacterial liquid is observed for 24 hours. The control drug tiamulin was assayed in the same manner as MIC at the lowest drug concentration that completely inhibited bacterial growth in the wells, and bacteria were significantly grown in the positive control wells (i.e., without drug). When single jump holes occur in the micro broth dilution method, the highest drug concentration that inhibits the bacteria is recorded, and if multiple jump holes occur, the test is repeated.
Table 3 shows MIC results, and shows that the target compound has good antibacterial activity on selected strains, has good inhibitory activity on drug-resistant staphylococcus aureus, and is particularly suitable for being used as a novel antibacterial drug for preventing and treating infectious diseases caused by human or animal or drug-resistant staphylococcus aureus or multi-drug resistant bacteria.
TABLE 3 in vitro bacteriostasis data
(2) Determination of Compound solubility
Compounds 2, 3, 15 and 19 were sulphate-treated with ritamicin sulphate as control. The solubility in water of each of them was measured by high performance liquid chromatography. The test results are shown in Table 4.
Table 4 sulfate solubility of compounds 2, 3, 15, 19 and ritamicin
| Compounds of formula (I) | Solubility (mg/mL, ph=7.0 in water) |
| 2 | 1.42 |
| 3 | 1.57 |
| 15 | 1.85 |
| 19 | 2.32 |
| Ruitamulin (Retapamulin) | 0.11 |
As can be seen from Table 4, the tested compounds all have good water solubility, which is superior to the solubility of the ritamicin salt, and improves the solubility of the pleuromutilin derivative, wherein the solubility of the compound 19 in the sulfate water reaches 2.32mg/mL.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (8)
1. A pleuromutilin derivative having a side chain of 1,3, 4-oxadiazole, characterized by being a compound of formula 2:
wherein R is furyl, thienyl, phenyl, 2-pyridyl, 4-pyridyl, pyrazinyl, and,
2. The pleuromutilin derivative having a 1,3, 4-oxadiazole side chain as claimed in claim 1, characterized in that:
the pharmaceutically acceptable salt is a salt formed by the compound of the formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
3. The pleuromutilin derivative having a 1,3, 4-oxadiazole side chain as claimed in claim 2, characterized in that:
the pharmaceutically acceptable salt has the following structural formula:
4. a process for the preparation of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain as claimed in any one of claims 1 to 3, characterised in that it comprises the steps of:
(1) Reacting pleuromutilin with p-toluenesulfonyl chloride to obtain an intermediate I with a structure shown in a formula 3;
(2) Reacting carboxylic acid serving as a raw material with absolute ethyl alcohol to obtain an intermediate II with a structure shown in a formula 4;
(3) Reacting the intermediate II prepared in the step (2) with hydrazine hydrate to obtain an intermediate III with a structure shown in a formula 5;
(4) Reacting the intermediate III prepared in the step (3) with carbon disulfide to obtain an intermediate IV shown in a formula 6;
(5) Further activating the intermediate I prepared in the step (1) by sodium iodide, and then reacting with the intermediate IV prepared in the step (4) to obtain the pleuromutilin derivative with the 1,3, 4-oxadiazole side chain shown in the formula 2;
the intermediates I, II, III and IV respectively have structural formulas 3-6:
5. use of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain as claimed in any one of claims 1 to 3 in the preparation of an antibacterial product.
6. Use of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain according to claim 5 for the preparation of an antibacterial product, characterized in that:
the antibacterial product is a medicine for treating infectious diseases.
7. Use of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain according to claim 6 for the preparation of an antibacterial product, characterized in that:
the infectious diseases are infectious diseases caused by infection of human or animals by drug-resistant staphylococcus aureus or multi-drug resistant bacteria.
8. Use of a pleuromutilin derivative having a 1,3, 4-oxadiazole side chain according to claim 6 for the preparation of an antibacterial product, characterized in that:
the medicament contains one or more pharmaceutically acceptable carriers, excipients or diluents.
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| CN114539241B (en) * | 2022-02-28 | 2024-06-04 | 西咸新区沣厚原创医药科技有限公司 | Pleuromutilin derivative containing thiazole-pyridine methyl aromatic heterocyclic quaternary ammonium salt side chain and preparation method and application thereof |
| CN114671865B (en) * | 2022-03-29 | 2024-06-04 | 西咸新区沣厚原创医药科技有限公司 | Pleuromutilin derivative containing thiazole-pyridinylalkyl quaternary ammonium salt side chain, and preparation method and application thereof |
| CN114634498B (en) * | 2022-03-29 | 2024-06-04 | 西咸新区沣厚原创医药科技有限公司 | Pleuromutilin derivative containing thiazole-pyridine benzyl quaternary ammonium salt side chain and preparation method and application thereof |
| CN114456160B (en) * | 2022-03-30 | 2024-02-23 | 西安康远晟生物医药科技有限公司 | Oxadiazole-pyridine quaternary ammonium salt side chain-containing pleuromutilin derivative with drug-resistant bacteria resisting activity, and preparation method and application thereof |
| US11905265B1 (en) * | 2023-10-13 | 2024-02-20 | King Faisal University | 3,4-dimethoxy-n′-(2-(5-phenyl-1,3,4-oxadiazol-2ylthio)acetoxy)benzimidamide as an antimicrobial compound |
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